The goals of this proposal are to develop new reactions based on the Prins cyclization and to apply these new reactions to the synthesis of complex natural products. New methods to be developed include the second generation Mukayama aldol Prins (MAP) reaction with unactivated alkenes. A new cascade cyclization reaction between enones and enol ethers has been discovered that will be investigated. The mechanism of the Prins cyclization will be studied, and the role of 2-oxonia Cope rearrangements will be investigated. The surprising axial selective in Prins cyclizations promoted by TMSBr cyclization will be studied both mechanistically and as a practical preparative procedure. Syntheses based on this new methodology include routes to calyxin I, a second-generation synthesis of leucascandrolide A, lasonolide A and kendomycin. Both leucascandrolide A and lasonolide A have shown potent cytotoxicity against human cancer cell lines, and the planned syntheses are more concise and efficient than any yet reported for these important compounds. The work described herein will advance the state of synthetic chemistry and provide new tools for organic chemists. These tools will facilitate the synthesis of many new structures that may be important as new pharmaceutical agents.